The treatment of chronic and non-chronic pain conditions has great importance in medicine. There is a worldwide need for effective methods of treating pain. The urgent need for patient-friendly and purposeful treatment of chronic and non-chronic pain conditions, especially the successful and satisfactory treatment of pain for the patient, is documented in the large number of scientific papers which have recently appeared in the field of applied analgesics and fundamental research work on nociception.
Conventional μ-opioids such as morphine are very effective in the therapy of strong to very strong pain and are of great importance for the treatment of pain. However, it may be advantageous if, in addition to the μ-opioid receptor, other opioid receptors (δ, κ, ORL-1) are influenced, as the pure μ-opioids also have undesirable side effects such as obstipation and respiratory depression, and may also lead to dependency. The opioid receptors δ, κ and ORL-1 are involved in the pain states (Opioids: Introduction, p. 127-150, Further Opioid Receptors, 455-476 in: Analgesics—From Chemistry and Pharmacology to Clinical Application, Wiley VCH 2002).
The ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory (Manabe et al., Nature, 394, 1997, p. 577-581), hearing capacity (Nishi et al., EMBO J., 16, 1997, p. 1858-1864) and numerous further processes. A synopsis by Calo et al. (Br. J. Pharmacol. 129, 2000, 1261-1283) gives an overview of the indications or biological procedures, in which the ORL1-receptor plays a part or could very likely play a part. Mentioned inter alia are: analgesics; stimulation and regulation of nutrient absorption; effect on μ-agonists such as morphine; treatment of withdrawal symptoms; reduction of the addiction potential of opioids; anxiolysis; modulation of motor activity; memory disorders; epilepsy; modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing the cardiovascular system; triggering an erection; diuresis; anti-natriuresis; electrolyte balance; arterial blood pressure; water retention disorders; intestinal motility (diarrhea); relaxation of the respiratory tract; and micturation reflex (urinary incontinence). The use of agonists and antagonists as anoretics, analgesics (also when administered with opioids) or nootropics is also discussed.
An object of the present invention is to provide pharmaceutical compositions which act on the opioid receptor system and are thus suitable for pharmaceutical compositions, in particular for the treatment of the various diseases associated with this system according to the prior art and for use in the indications mentioned therein.
The invention therefore relates to spirocyclic cyclohexane derivatives of general formula I,
wherein    R1 and R2 independently of one another represent H; CHO; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; respectively saturated or unsaturated, singly or multiply substituted or unsubstituted C3-8 cycloalkyl; or respectively singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkylor the radicals R1 and R2 together form CH2H2OCH2CH2, CH2CH2NR11CH2CH2 or (CH2)3-6,    wherein R11 represents H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; respectively saturated or unsaturated, singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or respectively singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;    R3 represents respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; respectively saturated or unsaturated, singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively unsubstituted or singly or multiply substituted aryl or heteroaryl; or respectively unsubstituted or singly or multiply substituted aryl, heteroaryl or C3-8 cycloalkyl bound by C1-3 alkyl group;    W represents NR4, O or Sand    R4 represents H; saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl; respectively substituted or unsubstituted aryl or heteroaryl; respectively singly or multiply substituted or unsubstituted aryl, heteroaryl or cycloalkyl bound by a C1-3 alkyl group; COR12 or SO2R12,    wherein R12 represents H; respectively saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; respectively saturated or unsaturated, singly or multiply substituted or unsubstituted C3-8 cycloalkyl; respectively singly or multiply substituted or unsubstituted aryl or heteroaryl; or respectively singly or multiply substituted or unsubstituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl; OR13 or NR14 R15;    R5 represents ═O; H; COOR13, CONR13, OR13; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-5 alkyl; saturated or unsaturated, unsubstituted or singly or multiply substituted C3-8 cycloalkyl; unsubstituted or singly or multiply substituted aryl or heteroaryl; or unsubstituted or singly or multiply substituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;    R6 represents H; F, Cl, NO2, CF3, OR13, SR13, SO2R13, SO2R13, CN, COOR13, NR14R15; saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl; saturated or unsaturated, unsubstituted or singly or multiply substituted C3-8 cycloalkyl; unsubstituted or singly or multiply substituted aryl or heteroaryl; or unsubstituted or singly or multiply substituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;or R5 and R6 together represent (CH2)n where n=2, 3, 4, 5 or 6, wherein individual hydrogen atoms may also be replaced by F, Cl, Br, I, NO2, CF3, OR13, CN or C1-5 alkyl;    R7, R8, R9 and R10, independently of one another, represent    H, F, Cl, Br, I, NO2, CF3, OR13, SR13, SO2R13, SO2OR13, CN, COOR13NR14R15; unsubstituted or singly or multiply substituted C1-5 alkyl, C3-8 cycloalkyl; unsubstituted or singly or multiply substituted aryl or heteroaryl; or unsubstituted or singly or multiply substituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;    wherein R13 represents H; respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl; respectively saturated or unsaturated, unsubstituted or singly or multiply substituted C3-8 cycloalkyl; unsubstituted or singly or multiply substituted aryl or heteroaryl; or unsubstituted or singly or multiply substituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;    R14 and R15 independently of one another represent H; respectively saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl; respectively saturated or unsaturated, unsubstituted or singly or multiply substituted C3-8 cycloalkyl; unsubstituted or singly or multiply substituted aryl or heteroaryl; or unsubstituted or singly or multiply substituted aryl, C3-8 cycloalkyl or heteroaryl bound by C1-3 alkyl;or R14 and R15 together form CH2CH2OCH2CH2, CH2CH2NR16CH2CH2 or (CH2)3-6;    wherein R16 represents H; saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl;    X represents O, S, SO, SO2 or NR17;    R17 represents H; C1-5 alkyl, saturated or unsaturated, branched or unbranched; COR12 or SO2R12;in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or an individual enantiomer or diastereomer; the bases and/or salts of physiologically acceptable acids or cations.
When combining various radicals, for example R7, R8, R9 and R10, and when combining radicals on their substituents, such as OR13, SR13, SO2R13 or COOR13, a substituent, for example R13, can assume different meanings for two or more radicals, for example R7, R8, R9 and R10, within a substance.
The compounds according to the invention exhibit good binding to the μ-receptor and also to other opioid receptors. Surprisingly, it has been found that the substances also have an affinity for binding site 2 of the sodium channel (BTX binding).
As a result, the compound class of general formula I is also suitable for use as a local anaesthetic.
The terms “C1-5 alkyl” and “C1-3 alkyl”, according to the invention, include acyclic saturated or unsaturated hydrocarbon radicals, which may be branched or straight-chained and unsubstituted or singly or multiply substituted, with 1, 2, 3, 4 or 5 C atoms or 1, 2 or 3 C atoms, i.e. C1-5 alkanyls, C2-5 alkenyls and C2-5 alkinyls or C1-3 alkanyls, C2-3 alkenyls and C2-3 alkinyls. Alkenyls have at least one C—C double bond and alkinyls at least one C—C treble bond. Alkyl is advantageously selected from the group comprising methyl, ethyl, n-propyl, 2-propyl, n-butyl, iso-butyl, sec.-butyl, tertiary-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl; ethylenyl (vinyl), ethinyl, propenyl (—CH2CH═CH2, —CH═CH—CH3, —C(═CH2)—CH3), propinyl (—CH—C≡CH, —C≡C—CH3), 1,1-dimethylethyl, 1,1-dimethylpropyl, butenyl, butinyl, pentenyl and pentinyl.
For the purposes of this invention the term “cycloalkyl” or “C3-8 cycloalkyl” denotes cyclic hydrocarbons with 3, 4, 5, 6, 7 or 8 carbon atoms, wherein the hydrocarbons may be saturated or unsaturated (but not aromatic), unsubstituted or singly or multiply substituted. With respect to cycloalkyl, the term also comprises saturated or unsaturated (but not aromatic) cycloalkyls, in which one or two carbon atoms are replaced by a heteroatom, S, N or O. C3-8 cycloalkyl is advantageously selected from the group comprising cyclopropyl, cyclobutyl, cyclopentane, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, and also tetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl, piperazinyl, pyrazolinonyl and pyrrolidinyl.
The term (CH2)3-6 is taken to mean —CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—, —CH2—CH2—CH2—CH2—CH2— and CH2—CH2—CH2—CH2—CH2—CH2.
The term “aryl”, according to this invention, denotes carbocyclic ring systems comprising at least one aromatic ring, but without a heteroatom in only one of the rings, inter alia phenyls, naphthyls and phenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls. The aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems. Each aryl radical can be unsubstituted or singly or multiply substituted, wherein the aryl substituents may be the same or different and in any desired or possible position of the aryl. Phenyl- or naphthyl radicals are particularly advantageous.
The term “heteroaryl” represents a 5-, 6- or 7-membered cyclic aromatic radical, which contains at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms may be the same or different and the heterocycle unsubstituted or singly or multiply substituted; in the case of substitution on the heterocycle, the substituents may be the same or different and in any desired, possible position of the heteroaryl. The heterocycle may also be part of a bicyclic or polycyclic system. Preferred heteroatoms include nitrogen, oxygen and sulphur. It is preferred that the heteroaryl radical is selected from the group comprising pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phtalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, wherein the bond to the compounds of general structure I may be effected by any desired, possible ring member of the heteroaryl radical.
In connection with “alkyl”, the term “substituted” according to this invention is taken to mean the substitution of one or more hydrogen radicals by F, Cl, Br, I, —CN, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-cycloalkyl, NH-alkyl aryl, NH-alkyl heteroaryl, NH-alkyl OH, N(alkyl)2, N(alkyl aryl)2, N(alkyl heteroaryl)2, N(cycloalkyl)2, N(alkyl OH)2, NO2, SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl aryl, S-alkyl heteroaryl, S-cycloalkyl, S-alkyl OH, S-alkyl SH, OH, O-alkyl, O-aryl, O-heteroaryl, O-alkyl aryl, O-alkyl heteroaryl, O-cycloalkyl, O-alkyl OH, CHO, C(═O)C1-6 alkyl, C(═S)C1-6-alkyl, C(═O)aryl, C(═S)aryl, C(═O)C1-6 alkyl aryl, C(═S)C1-6 alkyl aryl, C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl, CO2H, CO2 alkyl, CO2-alkyl aryl, C(═O)NH2, C(═O)NH-alkyl, C(═O)NH-aryl, C(═O)NH-cycloalkyl, C(═O)N(alkyl)2, C(═O)N(alkyl aryl)2, C(═O)N(alkyl heteroaryl)2, C(═O)N(cycloalkyl)2, SO-alkyl, SO2-alkyl, SO2NH2, SO3H, PO(O—C1-6-alkyl)2, Si(C1-6alkyl)3, Si(C3-8 cycloalkyl)3, Si(CH2—C3-8 cycloalkyl)3, Si(phenyl)3, cycloalkyl, aryl or heteroaryl, wherein multiply substituted radicals are taken to mean radicals which are either multiply, for example doubly or trebly, substituted on different atoms or the same atoms, for example trebly on the same C atom, as in the case of CF3 or —CH2CF3 or at different positions, as in the case of —CH(OH)—CH═CHCHCl2. Multiple substitution can take place with the same substituent or with different substituents. A substituent may optionally also in turn be substituted; thus —O—alkyl also includes inter alia —O—CH2—CH2—O—CH2—CH2—OH.
With respect to “aryl”, “heteroaryl” and “cycloalkyl”, according to this invention, “singly or multiply substituted” is taken to mean single or multiple, for example double, treble, quadruple or quintuple, substitution of one or more hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH2, NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl aryl, NH-alkyl heteroaryl, NH-cycloalkyl, NH-alkyl OH, N(alkyl)2, N(alkyl aryl)2, N(alkyl heteroaryl)2, N(cycloalkyl)2, N(alkyl OH)2, NO2, SH, S-alkyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl aryl, S-alkyl heteroaryl, S-cycloalkyl, S-alkyl OH, S-alkyl SH, OH, O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl aryl, O-alkyl heteroaryl, O-cycloalkyl, O-alkyl OH, CHO, C(═O)C1-6 alkyl, C(═S)C1-6 alkyl, C(═O)aryl, C(═S)aryl, C(═O)—C1-6 alkyl aryl, C(═S)C1-6 alkyl aryl, C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl, CO2H, CO2-alkyl, CO2-alkyl-aryl, C(═O)NH2, C(═O)NH-alkyl, C(═O)NH-aryl, C(═O)NH-cycloalkyl, C(═O)N(alkyl)2, C(═O)N(alkyl aryl)2, C(═O)N(alkyl heteroaryl)2, C(═O)N(cycloalkyl)2, S(O)-alkyl, S(O)-aryl, SO2-alkyl, SO2-aryl, SO2NH2, SO3H, CF3, ═O, ═S, alkyl, cycloalkyl, aryl and/or heteroaryl, on one atom or optionally on different atoms (wherein a substituent can, in turn, optionally be substituted). Multiple substitution takes place here using the same or different substituents.
The term salt is taken to mean any form of the active ingredient according to the invention in which it assumes or is charged with an ionic form and is coupled to a counter ion (a cation or an anion) or is in solution. This also includes complexes of the active ingredient with other molecules and ions, in particular complexes complexed by ionic interactions. In particular this is taken to mean (and this is also a preferred embodiment of this invention) physiologically acceptable salts, in particular physiologically acceptable salts with cations or bases and physiologically acceptable salts comprising anions or acids or even a salt formed with a physiologically acceptable acid or a physiologically acceptable cation.
The term physiologically acceptable salts with anions or acids is taken to mean, according to this invention, salts of at least one of the compounds of the invention—usually protonated, for example on nitrogen—as cation with at least one anion, which are physiologically acceptable—in particular when applied to humans and/or mammals. In particular, according to this invention, this is taken to mean the salt formed with a physiologically acceptable acid, namely salts of the respective active ingredient with inorganic or organic acids, which are physiologically acceptable—in particular when applied to humans and/or mammals. Examples of physiologically acceptable salts of specific acids are salts of: hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, maleic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoic acid, α-lipoic acid, acetyl glycine, phosphoric acid, maleic acid, malonic acid, hippuric acid and/or aspartic acid. Hydrochloride salt, citrate and hemicitrate are particularly preferred.
The term “salt formed with a physiologically acceptable acid”, according to this invention, is taken to mean salts of the respective active ingredient with inorganic or organic acids, which are physiologically acceptable—in particular when applied to humans and/or mammals. Hydrochloride and citrate are particularly preferred. Examples of physiologically acceptable acids include: hydrochloric acid, hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid, monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid, nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl benzoic acid, α-lipoic acid, acetylglycine, acetylsalicic acid, hippuric acid and/or aspartic acid.
The term “physiologically acceptable salt with cations or bases” is taken to mean, in the context of this invention, salts of at least one of the compounds according to the invention—usually a (deprotonated) acid—as an anion with at least one, preferably inorganic, cation, which are physiologically acceptable, in particular when applied to humans and/or mammals. The salts of the alkali and alkaline earth metals are preferred, and also ammonium salts, in particular however (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium salts.
The term “salt formed with a physiologically acceptable with cation” is taken to mean, according to this invention, salts of at least one of the respective compounds as an anion with at least one inorganic cation, which are physiologically acceptable, in particular when applied to humans and/or mammals. The salts of the alkali and alkaline earth metals are particularly preferred, as are ammonium salts, in particular (mono) or (di)sodium, (mono) or (di)potassium, magnesium or calcium salts.
In a preferred embodiment of the spirocyclic cyclohexane derivatives according to the invention    R1 and R2 independently of one another represent H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-8 alkyl;    or the radicals R1 and R2 together form a ring and represent CH2CH2OCH2CH2, CH2CH2NR11CH2CH2 or (CH2)3-6;    wherein R11 represents H; saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted C1-8 alkyl;
Particularly preferred are spirocyclic cyclohexane derivatives, wherein R1 and R2 independently of one another represent CH3 or H, wherein R1 and R2 do not simultaneously represent H.
Also preferred are spirocyclic cyclohexane derivatives, wherein    R3 represents respectively unsubstituted or singly or multiply substituted cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyridyl, pyrimidyl or pyrazinyl; respectively unsubstituted or singly or multiply substituted C5-6 cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bound by a saturated, unbranched C1-2 alkyl group;    in particular    R3 represents respectively unsubstituted or singly or multiply substituted phenyl, furyl, thiophenyl, naphthyl, benzyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyridyl, pyrimidyl, pyrazinyl or benzothiophenyl; respectively unsubstituted or singly or multiply substituted phenyl, furyl or thiophenyl bound by a saturated, unbranched C1-2 alkyl group;    Particularly preferred are spirocyclic cyclohexane derivatives, wherein R3 represents respectively substituted or unsubstituted phenyl, phenethyl, thiophenyl, pyridyl or benzyl, more preferably phenyl.
Also particularly preferred are spirocyclic cyclohexane derivatives, wherein R3 represents phenyl, unsubstituted or singly or multiply substituted by F, Cl, CN, OCH3, OCH2CH3, CH3, CF3 or OH, in particular 3-fluorophenyl and 4-fluorophenyl.
Also preferred are spirocyclic cyclohexane derivatives, wherein R5 represents H, branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl, or COOR13 and R6 represents H or C1-5 alkyl.
Spirocyclic cyclohexane derivatives are also preferred, wherein R7, R8, R9 and R10 independently of one another represent H; branched or unbranched, unsubstituted or singly or multiply substituted C1-5 alkyl; F, Cl, Br, I, CF3, OH, OCH3, NH2, COOH, COOCH3, NHCH3 or N(CH3)2 or NO2.
Particularly preferred are spirocyclic cyclohexane derivatives, wherein the radicals R5-R10 represent H.
Most preferred are spirocyclic cyclohexane derivatives from the group comprising    N,N-dimethyl-N-{4-phenyl-1′,3′,4′,5′-tetrahydro-spiro[cyclohexane-1,1′-pyrano[4,3-b]indol]-4-yl}amine    N,N-dimethyl-N-{4-phenyl-1′,3′,4′,5′-tetrahydro-spiro[cyclohexane-1,1′-pyrano[4,3-b]indol]-4-yl}amine triflate    N,N-dimethyl-N-{4-phenyl-1′,3′,4′,5′-tetrahydro-spiro[cyclohexane-1,1′-pyrano[4,3-b]indiol]-4-yl}amine citrate    N,N-dimethyl-N-{4-(4-fluorophenyl)-1′,3′,4′,5′-tetrahydro-spiro[cyclohexane-1,1′-pyrano[4,3-b]indol]-4-yl}ammonium triflate    N,N-dimethyl-N-{4-(3-fluorophenyl)-1′,3′,4′,5′-tetrahydro-spiro[cyclohexane-1,1′-pyrano[4,3-b]indol]-4-yl}ammonium triflate    N,N-dimethyl-N-{4-phenyl-spiro[cyclohexane-1,4′-1′,4′-dihydro-2′H-3′-oxa-9′-thiafluoren]-4-yl}amine    N,N-dimethyl-N-{4-phenyl-spiro[cyclohexane-1,4′-1′,4′-dihydro-2′H-3′-oxa-9′-thiafluoren]-4-yl}amine triflate    N,N-dimethyl-N-{4-(4-fluorophenyl)-spiro[cyclohexane-1,4′-1′,4′-dihydro-2′H-3′-oxa-9′-thiafluoren]-4-yl}ammonium triflate    N,N-dimethyl-N-{4-(3-fluorophenyl)-spiro[cyclohexane-1,4′-1′,4′-dihydro-2′H-3′-oxa-9′-thiafluoren]-4-yl}ammonium triflate    N,N-dimethyl-N-{4-phenyl-1′,4′-dihydrospiro[cyclohexane-1,4′-2′H-3′,9′-dithiafluoren]-4-yl}ammonium methane sulphonate    N,N-dimethyl-N-{4-phenyl-1′,4′-dihydrospiro[cyclohexane-1,4′-2′H-9′-oxa-3′-thiafluoren]-4-yl}ammonium methane sulphonate    N,N-dimethyl-N-{4-pyridine-1′,3′,4′,5′-tetrahydro-spiro[cyclohexane-1,1′-pyrano[4,3-b]indol]-4-yl}amine    N,N-dimethyl-N-{4-pyridine-1′,3′,4′,5′-tetrahydro-spiro[cyclohexane-1,1′-pyrano[4,3-b]indol]-4-yl}amine citrate    N,N-dimethyl-N-{4-phenyl-1′,4′-dihydrospiro[cyclohexane-1,4′-2′H-3 ,9′-dioxafluoren]-4}ammonium methane sulphonate    in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or an individual enantiomer or diastereomer; the bases and/or salts of physiologically acceptable acids or cations.
The substances according to the invention act, for example, on the i-opioid receptor that is relevant in connection with various diseases, so they are suitable as a pharmaceutical active ingredient in a pharmaceutical composition. The invention therefore also relates to pharmaceutical compositions containing at least one spirocyclic cyclohexane derivative according to the invention and optionally suitable additives and/or auxiliary agents and/or optionally further active ingredients.
The pharmaceutical compositions according to the invention optionally contain, in addition to at least one spirocyclic cyclohexane derivative according to the invention, suitable additives and/or auxiliary agents, therefore also excipients, fillers, solvents, diluents, dyes and/or binders and can be administered as liquid pharmaceutical preparations in the form of injection solutions, drops or syrups, as semi-solid pharmaceutical preparations in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols. The choice of auxiliary agents, etc., and the quantities thereof to be used depend on whether the pharmaceutical preparation is to be applied orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes. Preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral application, topical and inhalative application solutions, suspensions, easily reconstituted dry preparations and sprays for parenteral application. Spirocyclic cyclohexane derivatives according to the invention in a deposit, in dissolved form or in a plaster, optionally with the addition of agents to promote skin penetration, are suitable percutaneous application preparations. Forms of preparation which can be administered orally or percutaneously can release the spirocyclic cyclohexane derivatives according to the invention slowly. The spirocyclic cyclohexane derivatives according to the invention can also be administered in the form parenteral long-acting repositories such as implants or implanted pumps. In principle, further active ingredients known to the person skilled in the art can be added to the pharmaceutical preparations according to the invention.
The amount of active ingredient to be administered to the patient varies as a function of the weight of the patient, the method of application, the indication and the severity of the illness. Conventionally, 0.00005 to 50 mg/kg, preferably 0.01 to 5 mg/kg of at least one spirocyclic cyclohexane derivative according to the invention are applied.
With all of the above forms of the pharmaceutical compositions according to the invention it is particularly preferred if the pharmaceutical composition contains, in addition to at least one spirocyclic cyclohexane derivative, a further active ingredient, in particular an opioid, preferably a strong opioid, in particular morphine, or an anaesthetic, preferably hexobarbital or halothane.
In a preferred form of the pharmaceutical composition, a spirocyclic cyclohexane derivative contained according to the invention is present as a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar blend of the diastereomers and/or enantiomers.
The μ-opioid receptor, and also the other opioid receptors, have been identified in particular in the event of pain. Accordingly, spirocyclic cyclohexane derivatives according to the invention can be used for producing a pharmaceutical composition for the treatment of pain, in particular acute, neuropathic or chronic pain.
The invention therefore also relates to the use of a spirocyclic cyclohexane derivative according to the invention for producing a pharmaceutical composition for treating pain, in particular acute, visceral, neuropathic or chronic pain.
The invention also relates to the use of a spirocyclic cyclohexane derivative according to the invention for producing a pharmaceutical composition for the treatment of anxiety, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunction, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and/or drug and/or medicine abuse and/or dependency, sexual dysfunction, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, hearing difficulties, deficient intestinal motility, impaired nutrient absorption, anorexia, obesity, locomotive disorders, diarrhea, cachexia, urinary incontinence or as a muscle relaxant, anti-convulsive or anaesthetic or for co-administration in treatment with an opioid analgesic or anaesthetic, for diuresis or anti-natriuresis, anxiolysis, for modulation of motor activity, for modulation of neurotransmitter release and treatment of neurodegenerative diseases associated therewith, for the treatment of withdrawal symptoms and/or for reducing the addiction potential of opioids.
In this case it may be preferred in one of the present uses if a spirocyclic cyclohexane derivative used is in the form of a pure diastereomer and/or enantiomer, as a racemate or as a non-equimolar or equimolar blend of the diastereomers and/or enantiomers.
The invention also relates to a method for the treatment, in particular in one of said indications, of a non-human mammal or humans, which or who requires treatment of pain, in particular chronic pain, by administration of a therapeutically effective dose of a spirocyclic derivative according to the invention, or of a pharmaceutical preparation according to the invention.
The invention also related to a process for producing the spirocyclic cyclohexane derivatives according to the invention as stated in detail in the following description and examples. Particularly suitable here is a process, hereinafter called the main process, for producing a spirocyclic cyclohexane derivative according to the invention comprising the following steps,    wherein    X, W, R1, R2, R3, R5, R6, R7, R8, R9 and R10 have the meaning given for the compounds according to the invention of formula I,    and    R01 and R02 have the meaning given for the compounds according to the invention of formula I for R1 and R2 and in addition, independently of one another, can represent a protective group:

To produce the compounds of general formula Ia ketones of general formula A are reacted with heteroaromatics of general formula B with addition of acid or trimethylsilylesters thereof, for example trifluoromethanesulphonic acid trimethylsilylester, acetic acid, phosphoric acid, methane sulphonic acid or trifluoroacetic acid in a suitable solvent, for example dichloroethane, dichloromethane, chloroform, acetonitrile, diethyl ether or nitromethane.
Alternatively, production may also take place according to the following pattern, wherein X, W, R3, R5, R6, R7, R8, R9 and R10 have the meaning given for compounds according to the invention of formula I,    and    R01 and R02 have the meaning given for compounds according to the invention of formula I for R1 and R2 and in addition, independently of one another, can represent a protective group.

Spirocyclic cyclohexane derivates of general formula I, wherein X represents NR17 and R17 represents COR12 or SO2R12, can be obtained by the reaction of spirocyclic cyclohexane derivates of general formula I, wherein X represents NH, by reaction with an anhydride or an acid chloride with addition of a base, for example triethylamine. The reaction is preferably carried out with microwave irradiation.
Spirocyclic cyclohexane derivates of general formula I, wherein X represents SO or SO2, can be obtained by reaction of spirocyclic cyclohexane derivates of general formula I, wherein X represents S, with an oxidizing agent, for example H2O2.